The skin of the Central American poison frogs, Dendrobates pumilio, contains a variety of alkaloids, some of which are known cardioactive agents as described by Witkop in The Alkaloids, Page 200, Volume 24 (Eds. Arnold and Brossi). Unfortunately, however, these chemicals have not been employed for medical treatment because they are not practically obtainable from natural sources. One group, consisting of two structural distinct subgroups, termed pumiliotoxins A and B was discovered as early as 1967 and with their allo equivalents includes at least 24 members. While structural studies have shown that these toxins share the unusual (Z)-6-alkylideneindolizidine ring system which carries side chains at positions C-6 and C-8 with the C-6 chain being connected to the ring by an exocyclic double bond, there have been no reports detailing methods whereby pumiliotoxins A or B can be made, and only one describing the synthesis of a simple pumiliotoxin A alkaloid 251D. Pharmacological studies have shown that pumiliotoxin B is a considerably more potent cardioactive drug than pumiliotoxin 251D. Thus, a method which would permit the practical synthesis of pumiliotoxin B and related dendrobatid alkaloids would facilitate their use in the treatment of cardiovascular disorders.
Although there hve been no previous reports on the synthesis of pumiliotoxin B, two related but structurally distinct pumiliotoxin A alkaloids, specifically pumiliotoxins 251D and 237A have recently been synthesized. Neither the synthesis of pumiliotoxins 237A nor 251D, however, involve the use of the key indolizidine alcohol and aldehyde intermediates which is the subject matter of the present invention. Moreover, neither synthesis employs the use of the ylide used in the present invention to generate pumilitoxin B.
As stated previously, there is at present no known synthetic scheme whereby pumiliotoxins B can be generated. However, a recent report by the present inventor has described a method that is useful for the stereo controlled synthesis of the side chain connected to the (Z)-6-alkylideneindolizidine ring system, that is, a method for assembling the allyic diol functionality of pumiliotoxin B. This work was done on model chemicals that do not contain an indolizidine ring, specifically (2S,4E)-heptenones, and these chemicals have no known cardioactive property.